Numerous receptor-ligand interactions are involved in the induction, establishment and modulation of immune responses directed against antigens. At least two signals are necessary to activate a CD4 or CD8 T-cell response to antigen (Lenschow et al. (1996) Ann. Rev. Immunol. 14:233-258). The first signal is delivered through the T-cell receptor (TCR) by an antigen (typically a peptide) bound to a major histocompatibility (MHC) class I or II molecule present on the surface of an antigen presenting cell (APC). The second signal involves the binding of a ligand present on the surface of the APC to a second receptor molecule on the surface of the T-cell. This second signal is termed co-stimulation, and the APC ligand is often referred to as a co-stimulatory molecule.
During activation of CD4+ T-cells important co-stimulation is delivered by OX-40 receptor/OX-40 ligand interaction. The OX-40 receptor (“OX-40”) (Paterson et al. (1987) Mol. Immunol. 24:1281-1290; Calderhead et al. (1993) J. Immunol. 151:5261-5271) has been shown to be present only on antigen activated CD4+ T-cells in vivo (Weinberg et al. (1994) J. Immunol. 152:4712-4721; Wienberg et al. (1996) Nature Medicine 2:183-189) unlike the CD28 receptor, which is present on the surface of many sub-classes of T-cells (irrespective of whether they are activated or not). For example, OX-40 is present on activated CD4+ T-cells that recognize autoantigen at the site of inflammation in autoimmune disease, but not in the periphery. OX-40 has also been shown to be present on the surface of a percentage of CD4+ T-cells isolated from tumor infiltrating lymphocytes and draining lymph node cells removed from patients with squamous cell tumors of the head and neck and melanomas (Vetto et al. (1997) Am. J. Surg. 174:258-265). The OX-40 ligand, a member of the tumor necrosis factor (TNF) superfamily, has been shown to co-stimulate T-cells which have been activated with an anti-CD3 antibody (i.e., in a nonantigen-specific manner) (Godfrey et al. (1994) J. Exp. Med. 180:757-762). Despite the recognition of the costimulatory properties of the OX-40 ligand, its benefits have not previously been fully exploited to enhance an antigen specific immune response.